Sterilizing medical articles of polymeric materials can be performed by a number of methods, such as steam sterilization (autoclavation), radiation sterilization (electron beam (EB), .beta.- and .gamma.-radiation), ethylene oxide (EtO) and aqueous formaldehyde. Each method has its specific advantages and disadvantages and will be selected with respect to the chemical structure of the polymeric material. If the material is employed as a packaging material, the selection also depends on the characteristics of the enclosed goods.
A technical problem that requires especially careful consideration is the sterile packaging and storing of parenterally administerable fluids that both are sensitive to atmospheric oxygen during storage and incompatible with many polymeric materials and their additives.
In known manufacturing technologies, the most rigorous methods involve filling a bag with the medical fluid in the presence of an inert gas, sealing the bag and subjecting it to steam sterilization and thereafter placing it, still in an oxygen free atmosphere, with an oxygen absorber in an outer oxygen impermeable envelope. Such a process, as for example described in the U.S. Pat. No. 4,998,400, is, however, both laborious and resource consuming.
Oxygen absorbers have previously been successfully used for the packaging of oxygen sensitive medical fluids like amino acid solutions and fat emulsions. The absorbers have been positioned between an inner medical container made from a gas pervious polymer material filled with the medical solution and an outer enclosing sheet made of an gas impermeable material. Such packages are disclosed by e.g. the European patent specifications EP-A-0 093 796 and EP-A-0 510 687.
Sterilization by irradiation is a desirable alternative method to heat sterilization, since it will provide a simpler and less costly manufacturing process. It is, however, a technique that must be carefully considered, because of the chemical and physical alterations that can be induced in the polymeric material in the presence of atmospheric oxygen.
EP-B-0 218 003 discloses a radiation sterilized medical device enclosed in a gas permeable bag which is irradiated with .gamma.-radiation and thereafter placed in a gas impermeable wrapping member together with a deoxidizing agent. Both residual oxygen and ozone resulting from the gamma radiation will thereby be absorbed and because the entry of oxygen from the external environment is almost completely prevented, an oxygen-free condition within the wrapping is obtained. The purpose of the technique disclosed in EP 0 218 003 is primarily to prevent the "gamma"-odour associated with ozone.
The British patent specification 1,230,950 describes a similar method of sterilizing material packaged together with an oxygen scavenger with .gamma.-radiation.
The sterilizing methods according to these patent specifications may, however, lead to the formation of undesired and potentially deleterious degradation products originating from free radicals of the polymeric material and the small amounts of dissolved oxygen that remains in the polymeric material during the .gamma.-irradiation. The activity of the highly reactive free radical containing molecules may to a certain degree pervade the original polymeric structure of the material by bond cleavage and macroradical formation, thereby making the material discoloured or changing its mechanical properties.
In theory, a layered polymeric material with adhered or built-in oxygen scavengers, as disclosed in the Japanese patent applications JP 61104974 and JP 63152570, may at least partially the problems of secondary effects originating from dissolved residual oxygen in the material. In practice, the .gamma.-radiation will cause local overheating in the material that leads to thermal oxidation that destroys the oxygen scavengers.
Much industrial effort has been devoted to the search for non-colouring radiation systems, especially for medical devices made of polypropen. The chemically aggressive radicals or products thereof may also damage sensible medical fluids stored in containers made of irradiated polymers. This tends to be especially disadvantageous when the fluids consist of sensitive amino acid solutions and/or lipid emulsions containing polyunsaturated fatty acids that are intended to be stored for a considerable time period.
The various methods for stabilizing polymers against such primary and secondary events of occurring in materials exposed to high-energy radiation include electron and ion scavenging, energy transfer processes, radical scavenging and acceleration of radical decay. Such methods are normally costly and do not always introduce processes and compounds that are compatible with sensible medical products. There is a very restricted knowledge of how such compounds may interfere with sensitive fluids during storage. Moreover, in the field of pharmaceuticals, there is a general desire from medical authorities that additives in any form shall be excluded from products on the market. Besides that, only a few additives have been found in practice to reduce the number of radicals generated in a polymer by a given .gamma.-radiation dose. Most of these additives are unacceptable for use, especially for medical articles, because of their intense yellow discoloration. Some of them may possibly accelerate post-.gamma.-degradation. Another approach has been to use an additive, not to prevent radical formation, but instead to speed the (hopefully harmless) decay of these radicals. This concept of radical "mobilization" has been clearly shown to speed radical decay, and to improve long-term stability in the case of polypropen. It has been shown that the decay of macroradicals formed from irradiation of polypropen under vacuum is accelerated by PE-waxes, atactic polypropen and hydrocarbon, in order of increasing effectiveness. None of these additives is, however, preventing the ion-electron reactions or deactivating excited states, as they are formed during the irradiation.
An important necessity for medical equipment to be .gamma.-sterilized is the substantially complete absence of contamination. This effectively eliminates all colour-forming antioxidants such as phenols (yellow-brown products) or aromatic amines (red-brown products) from plastic medical articles, see D. J. Carlsson et al. in Radiation Effects on Polymers Ed. by R. L. Clough et al., ACS Symposium Series 475,1991.
Hindered amines such as those based on 2,2,6,6,-tetramethylpiperidine operate as antioxidants at ambient temperatures in light-stabilization packages. Furthermore they and their products are colourless or only very weakly absorbing. These aliphatic amines have been previously shown to function as stabilizers to post-.gamma.-irradiation oxidation of polyolefines, a phenomenon explained on page 433, Chapter 26 "Stabilization of polyolefines to Gamma Irradiation" in the above cited D. J. Carlsson et al.
The irradiated polyolefin will, due to the production of free radicals among other compounds form hydroperoxides, which may be decomposed under the formation of even more free radicals. Highly efficient stabilizer combinations might possibly suppress oxidation to the point where atypical hydroperoxide products dominate. Post-irradiation oxidation is largely dependent upon initiation by the slow thermal decomposition of the hydroperoxides. Hydroperoxide decomposition by an additive, such as hindered amines, will also prevent this oxidative degradation. However, in medical applications all such additives are generally avoided, since they tend to discolour the articles and may migrate from the material and consequently introduce a toxicity risk.
The following description, given in order to clarify, the primary and secondary events taking place in polymers during, and after radiation sterilization, is based on the teachings by D. J. Carlsson et al. in Radiation Effects on Polymers Ed. by R. L. Clough et al., ACS Symposium Series 475, 1991, which hereby is incorporated by reference.
The primary radiation process appearing from irradiation of polymers can produce a number of different reactions, such as crosslinking, backbone scission and hydrogen evolution. Various chemical products can result from the occurrence of the complex cascade of events such as reactions (1)-(6) below, which are typical of gamma-irradiation. ##STR1##
At room temperature, the ion-electron recombination occurs quickly enough to give highly excited states (P*) and cations. At low temperatures (&lt;-100.degree. C.), ejected electrons may be trapped in the polymer matrix. The excited states dissipate some of their excess energy by bond scission to give free radicals. The scission of C--H bonds is favoured over C--C backbone scission.
Secondary reactions in irradiated polymers appear when the free radicals produced in reactions (5) and (6), above, lead to the formation of chemical products, commonly associated with radiation effects. The combination of macro-alkyl radicals or their addition to unsaturated sites leads to chain branching and/or crosslinking. Hydrogen atoms mainly abstract from the polymer chain to give molecular hydrogen and fresh macroalkyl radicals (reaction (7)). ##STR2## In some polymers, main chain scission is followed by monomer elimination. Macroradical combination results in crosslink formation (reaction (8)). ##STR3## Unsaturation is a major product from irradiated polyolefins and is believed to result from migration of radical sites by an inter- and intra-molecular hydrogen atom transfer until two sites come together. Unsaturated products with conjugated double bonds resulting from radiation can have an undesired discoloured appearance. ##STR4##
In the absence of oxygen, the net result of irradiation is the composite result of reactions (5)-(9) so that crosslinked gel or a degradation of molecular weight results. The behaviour of various polymers irradiated in the absence of oxygen may be generalized into those which crosslink during irradiation; polyethylene, poly(methyl acrylate), poly(acrylic acid), polystyrene) and those which degrade (poly(methyl methacrylate), poly(methacrylic acid), poly(.alpha.-methylstyrene), poly(butene-2). Polypropen undergoes both scission and crosslinking. Crosslinking increases the stiffness of plastics and can render them inextensible. Poly(olefin sulphones) have been shown to be exceptionally sensitive to .gamma.- or electron-beam radiation and can be used as short-wavelength photoresists. Chain scission also leads to embrittlement, but the effect of direct, radiation-induced scission in commodity polymers is normally minor compared with oxidative chain scission.
Because of its biradical nature, O.sub.2 reacts at close to the encounter frequency with carbon-centred radicals to give peroxyl radicals, by reaction (10). A relatively slow hydrogen abstraction from the polymer matrix by the peroxyl radicals, reaction (11), completes a cycle of reactions which cause the progressive oxidation of the polymer. ##STR5## The first molecular product, the hydroperoxide group, is thermally unstable and cleaves readily at the O--O linkage to give a pair of radicals and so leads to a branching, thermal oxidation during storage after irradiation. This effect is of major concern when sterilizing medical equipment, implants, etc. by .gamma.-radiation.
The loss of physical properties in many polymers containing aliphatic backbone substituents results from the .beta.-scission of alkoxyl radicals, reaction (12). The alkoxyl radicals are formed by hydroperoxide decomposition. ##STR6## They are also formed in the complex self-reaction of peroxyl radicals which may terminate the radicals. Elongation at break has been shown to be appreciably more sensitive to degradation than tensile strength.
The radiation sensitivity of polymeric materials is generally affected by impurities, additives, dose rate, sample thickness and morphology. For example, the highly oriented, chain-extended morphology in highly drawn PE fibres is much more .gamma.-irradiation-resistant than the usual melt-quenched semicrystalline morphology. This results both from restricted O.sub.2 diffusion and effects on radical decay rates. It is therefore complicated to predict the marked effect of the dose rate.
It is the primary object of the present invention to reduce the secondary processes appearing in polymeric material during and after sterilizing dosages of .gamma.-irradiation due to the presence of oxygen. It is of especial advantage to be able to eliminate the discolouring and the physical changes and degradation of polymeric materials that frequently appears after the use of conventional sterilization techniques.
A purpose with the present invention is also to obtain a safe and reproducible sterilization of sensitive medical objects without being dependent on expensive methods like evacuating air and introducing inert gases and steam sterilisation.